Degenerative joint disorders, such as arthritis, affect a substantial percentage of the US population and have a significant economic burden. The focused use of disease modifying drugs and cellular Strategies for tissue regeneration offer great potential to treat these disorders;however, the safety and efficacy of these treatment strategies must first be evaluated in pre-clinical models. The purposes of this proposal, and the career aims of the principal investigator, are to create and refine techniques to evaluate joint function and symptoms in pre-clinical, animal models of arthritis and to investigate the potential for disease-modifying therapeutics to modify functional and symptomatic sequelae associated with arthritis. This proposal begins with the mentored phase where interleukin 1p (IL-lp) overexpression in the knee joint will be used as a rat model of unilateral inflammatory arthritis. The functional and symptomatic sequelae of this arthritis will be evaluated using custom-designed gait and pain sensitivity tests. Moreover, two ILIp antagonists, interleukin 1 receptor antagonist (111 Ra) and soluble interleukin 1 receptor type II (slHRII), will be evaluated for their ability to modify functional and symptomatic sequelae associated with knee arthritis. The PI will then transition skills and knowledge gained during the mentored phase to the study of temporomandibular joint (TMJ) disorders and their functional and symptomatic sequelae. In the independent stage, techniques and methods to assess the sequelae of TMJ disorders will be developed for rodent models, including systems to evaluate orofacial sensitivity, bite force, dietary habits, and sleep patterns. The intra-articular ILip over-expression model will then be adapted to initiate TMJ arthritis, and the developed technologies will be applied and assessed for their ability to modify the associated functional and symptomal sequelae. This proposal addresses the developments of novel treatment and assessment strategies for knee arthritis and TMJ disorders, drawing significantly on the PI's experience in TMJ research and the mentor institution's expertise in osteoarthritis and drug delivery. Moreover, this research plan will assist the PI in transitioning to a faculty position and establish an independent research program evaluating therapeutic interventions for TMJ disorders and degeneration.